The subject invention relates to methods for synthesizing 1-aminohydantoin compounds, using a solid-support resin to facilitate purification of intermediates.
Resin based chemistry methods have blossomed the past decade, and have proved to be highly useful for multi-step syntheses.
Interest in compounds having the 1-amino variant of the hydantoin nucleus (1-below) stems from the demonstrated commercial significance as anti-infective (e.g., nitrofurantoin (2)), skeletal smooth muscle relaxant (e.g., dantrium (3)), anti-arrhythmic (e.g., azimilide (4)), and other interesting pharmacological diversity (e.g., prostaglandin D receptor agonist (5)) of different species. 
Furthermore, the 1-aminohydantoins contain the aza surrogate of amino acids (i.e. hydrazino acids), and aza amino acid replacements have pharmacological significance in many therapeutic areas. This aza replacement adds significantly different chemical and physical properties to the hydantoin ring system; one example of this is stable imine formation at the 1-amino position (semicarbazone-like).
Currently known solid phase based hydantoin routes that utilize cyclizative cleavage are disclosed in: (a) Dewitt, S. H.; Kiely, J. S.; Stankovic, C. J.; Schroeder, M. C.; Reynolds Cody, D. M.; Pavia, M. R.; Proc. Natl. Acad. Sci.,, vol. 90 (1993), pp. 6909-6913; (b) Dressman, B. A.; Spangle, L. A. Kaldor, S. W.; Tetrahedron Lett., vol. 37 (1996), pp. 937-940; (c) Hanessian, S.; Yang, R.-Y.; Tetrahedron Lett., vol. 37 (1996), pp. 5835-5838; (d) Kim, S. W.; Ahn, S. Y.; Koh, J. S.; Lee, J. H.; Ro, S.; Cho, H. Y.; Tetrahedron Lett, vol. 38 (1997), pp. 4603-4606; (e) Matthews, J.; Rivero, R. A.; J. Org. Chem., vol. 62 (1997), pp. 6090-6092. For an example of amine displacements on xcex1-bromo resin esters, see: Scott, B. O.; Siegmund, A. C.; Marlowe, C. K.; Pei, Y.; Spear, K. L.; Molecular Diversity, vol. 1 (1995), pp. 125-134.
Solution based chemist methods for making 1-aminohydantoins are disclosed, for example, in European Patent Application No. 0 126 849 of the Wellcome Foundation, inventor Caldwell, published Dec. 5, 1984.
The subject invention involves processes for making 1-aminohydantoin compounds: 
using a solid-support resin having a linking moiety capable of reacting with carboxylic acids and attaching them to the resin, comprising the following steps:
(a) preparing resin-bound, protected xcex1-hydrazinyl esters;
(1) by reacting the resin with xcex1-bromo carboxylic acids; then with a protected hydrazine; or
(2) by reacting the resin with protected xcex1-hydrazinyl carboxylic acids;
(b) preparing resin-bound imines by removing the blocking group from the hydrazinyl moiety of the xcex1-hydrazinyl esters, then reacting the unprotected hydrazinyl moiety with aldehydes or ketones;
(c) preparing resin-bound secondary ureas;
(1) by reacting the resin-bound imines with p-nitrophenylchloroformate or triphosgene, then with primary amines; or
(2) by reacting the resin-bound imines with isocyanates; and
(d) preparing the 1-aminohydantoin compounds by removing the resin-bound secondary ureas from the resin and cyclizing them.